PROJECT SUMMARY/ABSTRACT Progressive accumulation of microtubule-associated protein (tau) is a defining feature of Alzheimer's disease (AD) and a number of other disorders termed tauopathies. Recent studies from our laboratories, confirmed by others, demonstrated that tau oligomers constitute distinctly toxic and pathologically significant tau species able to spread in tauopathy brain, likely through inter-synaptic transmission. However, precise investigation of tau oligomer spreading is hindered by the complexity of the neuronal network. Methods to effectively diagnose AD and other tauopathies at early stages and monitor their progress are also lacking. In addition to cognitive abnormalities, AD patients show visual anomalies. In this application, we will test the hypothesis that tau pathology in the retina may predict tau-related dysfunction in the brain, making it an excellent platform to study the propagation of tau oligomeric strains, detect and monitor the progression of AD and other tau-related disorders, and evaluate the efficacy of our newly developed tau oligomer-specific monoclonal antibodies (TOMAs) at targeting different tau oligomeric strains. Outcomes from this study will provide clear pathways of oligomer spreading and aid in the development of novel approaches to monitor and treat tauopathies.